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BTXA™ Botulinum Toxin Type A

Anti-Aging TOP Secret

-=>PROSIGNE" LANTox REoux• Lanzo~: LIFT~ IJ@U.J({fi HU&H 111111111 1111111111111 1111111111111 111111111111111111111

Hugh Source Ontemational) Limited

BTX.A~ Botulinum Toxin Type A .

Mode of Action BTXA Molecular Mechanism of Action

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BTXA, Botulinum Toxin Type A, inhibits release of acetylcholine at presynaptic membrane of nerve terminals, resulting in muscular flaccid paralysis.

History of BTXA History of BTXA - BTXA and the American brand share the same Clostridium botulinum bacteria type A Hall Strain

Dr. Scott developed Oculinum•.

Oculinum• was manufactured by Oculinum

~ Inc. and distributed by Allergan Inc. in late 1970s.

The Allergan Inc. bought Oculinum Inc. from Dr. Scott ~ in 1991 and changed the brand name of Oculinum• to the American brand.

University of Wisconsin, USA Same Clostridium botulinum bacteria

type A Hall Strain

T T

Dr. Scott Prof. Sugiyama

T T

Oculinum• Dr.Yinchun Wang

T T

The American brand

BTXA

~

~

Dr. Scott & Prof. Hiroshi Sugiyama did research in t he University of Wisconsin, USA. Dr. Yinchun Wang was a visit scholar in t his university.

Prof. Sugiyama f rom University of Wisconsin donated the Clostridium botulinum bacteria type A Hall St rain to Dr. Yinchun Wang in 1984.

Dr. Wang is t he developer of BTXA in the l anzhou Institute of Biological Product of China w ith the bacteria Hall Strain obtained from the University of Wisconsin. The package inserts of Oculinum • as well as the American brand nowadays still quoted Dr. Yinchun Wang's research paper as their references.

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. BTX·A 'M. .: .. :··:: '.:·. Botulinum Toxin Type A • · · · · .'· :· :,,· . . .

• • • • • • -c~.""-

Evidence on the Clinical Efficacy and Safety of BTXA Compared to the American Brand

The treatment with BTXA is considered the golden standard in both Blepharospasms (BS) and Hemifacial

spasm (HS).

In A double-blind, randomized, crossover study of BTXA versus the American brand in patients with blepharospasms

and hemifacial spasm', the selected patients, all with HS or idiopathic BS, were followed in two periods for at

least three months.

The study evaluated the subjective global improvement, response onset, efficacy duration, and incidence and

severity of adverse events.

In all analyzed parameters, t here were no significant differences between the two drugs. It has been concluded

that BTXA and t he American brand are comparable with respect to efficacy and safety for the treatment of

blepharospasm and hemifacial spasm.

Safety Assessment

A more than five years' continuous safety

monitoring on BTXA application was carried out in

Brazil and respective Periodic Safety Update

Report (PSUR) was issued in Jan 20092.

During the period covered (Jun 2003- Dec 2008),

about 300,000 cases had been treated with BTXA

Reported satisfactory safety result

less than 1% occurence of adverse events

Overall adverse event rate is classified as uncommon. Most of the reported scenarios were also expected in

other brands of botulinum toxin type A.

BTXA ·treatment is C!Jntinuously unde~ Safety monitoring of Health. Authorities

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Botulinum Toxin Type A injections were the #1 non-surgical cosmetic procedure and the #1 cosmetic

procedure overall for the sixth year in a row3•

Efficacy vs Long - lasting Effects of BTXA in Facial Wrinkles Treatment

94°/o 92°/o ~ The satisfactory rate reached more than

90% in 14 days after injection4

82°/o 76°/o - ~ 50% patients maintained satisfactory

result up to 6-month period4

50°/o ~ Only 1% of the patients reported much

pain or burning upon the injection and

no patients reported significant

post-injection pain4

~ Conclusion: BTXA was deemed safe,

well tolerated and reached good

satisfactory levels4

3 days 14 days 45 days 90 days 180 days

References:

1. Costa J. Rieder C. et 8/. A double·bir1d. randomtsed. crossover study of Pros.lgna versus Botox n patients with blepharospasm and hamlfacla.l spasm. Ctn Neuropha1T110001. 2007;30:39-42.

2. Drug SafetY Report·Proslgne ®(Botulinum Toxin Type A). Jar1 2009. Hugh Source (lnt'O Ltd. Data on fie.

3 2007 Amellcan Society of Aesthetic Plastic Surgery (ASAPS) Cosmetic Surgery National Data Bank Statistics.

4. TalaJico S. Bgabn E. Pecora cs. Ferreira LM. Orofino A, Godoy A. et sf. Open· label. Prospecll\le, Multicenter. Mu~ldisclplinary Phase Ill Study to Evaluate U10 Elficacy and Toletabllty or

Prosigne (8otoJinum Toxin Type A) In the Allsthetlc Treatment of the Upper third of U10 Face In Patients with Facial Wrinkles. Data on file.

BTXA™ Botulinum Toxin Type A

Anti-Aging TOP Secret

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HU&H 1111 111111111 111111111111 11 11 11111111 11 1111111111111 11111111 Hugh Source (International) Umitl'd

Application areas

Forehead lines

Vertical glabellar lines

Horizonta l glabellar lines

Crow's feet (each side)

Perioral rhytides

Horizontal platysma!

bands (each band)

Masseter muscle

hypertrophy (each side)

Calf muscle hypertrophy (each side)

Frontalis m .

Nasalis m.

Levator labii superioris alaeque nasi m.

Levator labii superioris m.

Dose per site

2-4 u 4 U

4 U

2 U

1 -2 u 3-5 u

Man 10 -13U

Woman 7- 10 u su

• •

No. of sites Total dose Injection depth

5-10 10-20 u SC/IM

4 16 u SC/IM

1 4U SC/ IM

3-6 6-12 u sc 4 4-8 u Superficial

3 12-15 u IM

3-4 30-40 u IM:2-3 em

3-4 20-30 u IM: 1 - 1.5 em

20-30 100- 1 sou IM: -2cm

' . ·' .

Sites . . .

• •

Corrugator supercillaris

Corrugator m .

Levator anguli oris m.

Risorius m. ~

Orbicularisorism. ~ Depressor anguli oris m. ----

Depressor labii inferioris m. ~-:--~-..:. ___ _:

Mentalism. ~----==::::.

Injection depth e oeep e Middle e Superficial

Corrugator supercilli m.

Depressor supercilli m .

Medial palpebrallig

Anomalous nasi m.

Transverse portion of nasalis m .

Levator labii superiors alaegue nasi m.

Levator labii superioris m .

Zygomaticus minor m .

orism.

Galea aponeurotica

Temporalis

Depressor anguli oris m .

• Ask the patient to close the j aw tightly to show the masseter muscle • Use 23G needle to inject at the deeper portion of muscle

Information for injection

~ Dose of each site:

• Man: 10 - 13 U

• Woman: 7-10U

~ No. of sites: 3 - 4 each side

~ Total dose for each side:

• Man: 30-40 U

• Woman: 20 - 30 U

~ Depth: Intramuscular

• Man: 2 - 3cm

• Woman: 1 - 1.5 em

• Avoid injection to the origin site and upper portion to prevent cheek depression • Space the inject ions 2 em apart

Lateral head > Gastrocnemius Medial head

Information for injection ~ Dose of each site: 5 U

~ No. of sites: 20 - 30 each side

~ Tota I dose: 1 00 -150 U each side

~ Depth: Intramuscular {-2 em}

• Carry out intravenous sedation w it h Ketamine • Mark the outline contour of calf muscle when the patient is raising heel for tip-toeing

Classical locations of hyperhidrosis: face, underarm, hands and feet

Before injection:

An iodine starch test can be performed to ascertain the inject ion areas

Steps: 1. The areas to be evaluated are covered with castor oil & iodine in a 1 :9 proportion

2. The areas are sprinkled by potato starch

3. The areas of active sweating turn black

• This test should be carried out prior to regional nerve blocks or the use of topical anaesthetics

• It is helpful to draw a grid on the skin to mark the injection fields

For palms and soles:

• The dose varies from patient to patient and depends on the size of the hyperhidrotic area to be injected

• In plantar hyperhidrosis, the lateral and medial edges of the foot may need additional injections

• The main limitation is that most patients find the injections painful and may require regional anesthesia via median and

ulnar nerve blocks for palms and sural and posterior tibial nerve block for soles

• Alternatively, the area can be rendered relatively pain free by prior application of anesthetic cream under occlusion, iontophoretic application of lidocaine, or cryospray

Location Dose

Palms 50-100 U I palm

Soles 50-1 00 U I sole

Axillae 50 U I axilla

Palms

Inject lntradermally

Approximate depth of 3 mm

Avoid intramuscular injections

Injections are scattered every

1.5 - 2 em on the palm of the

hand and on the fingertips, tips

and webs of hand

Concentration Total injection sites

2- 2.5 U I 0.1 ml I site

2-2.5UI0.1 mllsite Depends on the size of the hyperhidrotic area

2.5 U I 0.1 ml I site 10-15 sites I axillae

5 U I 0.2 ml I site

Soles

Inject intradermally

Approximate depth of 3 mm

Avoid intramuscular injections

Injections are scattered every

1.5 - 2 em on the sole, sides of

the sole and will be placed in

the webs between the toes and

on the tips of the toes

Axillae

Inject intradermally

Approximate depth of 3 mm and at a 45• to

the skin surface

Avoid intramuscular injections

Injection to multiple sites approximately

1.5 - 2 em apart

If injection sites are marked in ink, do not inject BTXA directly through the ink mark to avoid a permanent tattoo effect

Storage condition:

Storage temperature Shelf life

Dilution table:

Before reconstitution 2°C to soc o r -20°C to -soc

2 or 3 years after lyophilization

After reconstitution 2°C to soc, do not freeze

Use within 4 hours ideally

Concentration (U/ 0.1 ml) Volume of diluents (ml) added

10.0 U I 0.1 ml

5.0 U 10.1 ml 4.0 U 10.1 ml 2.5 U I 0.1 ml 1 .25 U I 0.1 ml

SO Uvial O.Sml

1.0 ml

I 2.0ml 4.0ml

100 Uvial 1.0 ml

2.0 ml 2.5 ml 4.0 ml 8.0 ml

Reconstitution techniques:

Step 1:

Step2:

Step3:

Use a 21 G needle and an appropriately sized syringe to draw up appropriate amount of 0.9% sterile saline without

preservative. Insert the needle into glass vial gently and slowly inject to avoid bubble formation. Discard the vial if

a vacuum does not pull the diluents into vial.

Gently rotate the vial (do not vigorously shake the vial) to avoid bubble formation which may affect the potency

of toxin.

Draw the mixture back into the syringe. Inject the mixture into muscle by using appropriate needle tip for

injection.

Basic injection techniques: ~ Remove any make-up on the patient's skin and wipe the sites with alcohol swab. Allow to dry

~ Evaluate the bulk of muscle contraction at the proposed injection site

~ After aspiration of BTXA solution, remove the 21 G needle t ip and attach a 30G needle tip in order to minimize discomfort to

patient

~ Clear the air bubble from the syringe using minimal agitation before injection

~ Advise the patient to relax during injection

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Post-injection: • Press on the site with a tissue immediately after the injection for minutes to minimize bruising

• Any bruising that occurs should be treated immediately with ice pack

• No other treatments or massage unless otherwise specified

• Advise patient to take rest for 15 minutes before returning to normal activity

Contraindications: ~ Pregnant and breast feeding women

~ Hypersensitive patients

~ Heavy forehead furrows with slight ptosis

~ Redundant facial skin

~ Unrealistic goal and expectations

~ Infection or tumor at the proposed injection sites

~ Long-term usage of anticoagulant or patients with dysfunction of blood coagulation

~ Unstable mental state

~ Patients who are taking aspirin, aminoglycosides antibiotics (eg: gentamicin), aminoquinolines, cyclosporine,

0-penicillamine within two weeks prior to injection

How to avoid antibody formation? • Use minimum effective dose

• Keep at least 2 to 3 months interval between injections

• Avoid booster injection

• Inject no more than 300 units in 3 months

Effectiveness: • The onset time is 1 to 2 days for most of the patients

• Best effect will usually be attained 1 to 4 weeks after injection

• After 3 to 4 months, effectiveness will gradually fade, but the overall efficacy of BTXA can be maintained for 6 to 8

months

• According to many reports, the duration of effectiveness increased after repeated injections

• Younger patients with more elastic skin will have a longer effect

Potential risks: Among all the cases of BTXA cosmetic applications, severe adverse reaction was rarely reported.

• Bruising- resolve in 7 to 10 days

- Avoided by not taking aspirin prior to injection

Ptosis- resolve within a few weeks

-Avoided by injection at least 1 em above the eyebrow and no massage after injection

• Ecchymosis & oedema

• Tightening of forehead

• Mild nausea

• Pain at the injection sites

• Erythema

• Cyanosis

• Unnatural facial expression

Most side effects are transient and will disappear spontaneously after 1-2 weeks

BTXATM Botulinum Toxin Type A

TXA ...

BTXA BT A ~Botultnum Toxin Type A for lnjectio; -

" 11'1 Afo.

100 units x 1 vial 50 unltl )C I .. .,. .-

national} Ltd

Sole A~nt: Hugh Source (International} Ltd.

100 units X 1 .b I .,.,.. -

BTXA(Il011..Uf.JMTOXINT'II'C.AI OUC:RIPTION BTl<A (Bolull""" Toxin ,.,.l'l b o 1101118. ~bmOI I)I.IW«< _....,_A.---Oleeouclo OO<Inol <heeutt ... ol <he HOI molnoiCiolltldlum __ .,a..-..coo<elr*lg ttyplicaM .-d y8ISt eJLhCt. A_... of p.li~ procec:ln W81'8 t!ken to lotl'n t1 cry&leJIItll CXKTl,_ oonslstfrG ol h ~ t9' mc::Mio.ilf ~ loxln prot4ll1 and en assoclftt8d l1~1tltW!. Af't81 Ht~ end da'/led U. ~ ~ an IIIIXU'Ite

emount oJ h ste'llll:tnd J).2 n1cro'W) 10Xf\ Wlrli ad08d to a aolutb1 oonte.nlnQ go&Mn doxttan IUCIOM. hn ~ Eech Yel of BTXA cont11n1 100 Or 50 urata (U) ol C. bOtl~l toxltl t)pl A. 6 mg of Qllto!n. 26 rrg d dlx!Jan end 26 fTCJ d sucroll. o.Att 'M1h stiJt'tt rc:nn11 ua .. ~to dllk1nt needs befont using. n'M while bOlt proc1ICt t1..m1 .a be OOb18u or ~ ~ ICilJto'1 n~• the NIOOI'lltltutoo. One unit (U) ot STXA OOttespondl., 1 l.Ot50 of Boll*un Tc:Dei'I1'1PIA. Wllt bang ""~~ii"AO--.BJX.\CW<fblock.........,UIC ..... COilCl.,.,bymb.<llg<he •-ol0001)1d1011noendOhOoabo.,._.,.,muselet<ICCidi*W,Sis. INOICATIONS BTl<Aialrdce<Odb11leu-OI"""'*-·-­tl ~~ tnd Dnli t)'P8S d ~ ..,aaeey b ecute paralytic atJWJ!Jil'IUI, oomf1entatrat.nml&. s1JabllmUS C8UI8d by lfiCb:ltw ~and lttllbamus v.tllctl CM tlOt be comK:t8d tfWl9l opef'eiJJn, USAGE AHO DOSAGE PoshJon tor l~lon

Fe>'"'"'"""""""' Oloir1oc0on_,.,ba,_.,.,"""""""'~ •• '"""''" po,.aol '*""""""'""'"Ids. I.e talci0g4 oo5pohsol-lnlo01blc>- OQ.I o1 model""' lo<01o1 or "'"'"'"""'""'"'"'~'"""· fOI--·- ... _"""""'""' obcMI.-oiwpohlon-.--lr'<l--.ldbo!IIVOnnuom~~SC<..,Iy.BDCAmoybagJwno<11leOO<Uol""'_"'_·_lpoo tlt<ilow&o·jowoc:oOitfngloU18 dls ...... fOiattablmua'OlOBJX.\II-~•-­neect•war. ~~a~ !.l'lde' topical anmtll8Siaof0.6% [.)ac:artla, The~ i11.o11Xtta0Cl.8 frlJidlsaa~ ecc:otllng to the type and position of S1rab:smus. Oo .... For~rdtwnt!ciaf$p8Sm.lhe lfiecdon ooUd be ~ ~ abcMJ ~ The Wi81 ciOM d each point Is 2.5 U I 0 05 m or 2.5 U I o. 1 m. If the..-. tr8ldmin: ~ conllder8d fnsuft'dert one W98k lstfJ/1, a sL4)JJI9rnent81Y ''~ ntay bv QtMm. DcU* cb8 of~ U /0.1 ,., ~ b6 ~ lo ~~ patwu. &.« N hi'.a:JOn d UX8f be ol 56 U tor one lnjoctiO!l and 200 U lor one month Should t'IO( be exoeeded. For stral:li:smus: tor Y8fOC'&I 8r'ld hoftzoota! tnJsdo slrabiSI'r'l.ls oC less th8n 20 pr".sm clopcers. h l'ti!ll Close no each rn.ISde is 1 25-2.5 U; Ia" ~ snbl:smt.a. d 20-40 priam clopt•s. the in.t:al dose ~to ee.ch muscle Ia 2.5 U; tor tubxnt.ll &tt'llltamA:ol .40-!10 prism dcpl:.-s, h 'rita dose Into MCh 1nusci8 iJ 2.5 U and can be incf88..w (to 5JJ NCfl11N) dBp6rdng en the~ toe J~Wi. VI Cl1lft"3l f8"'JJII pera-,.u 1estac1 tot R'O'e thM one month. 1 .25-2.5 u dOS8 ooJd 00 lr\laCted no miCill!ll ,eaus_ n. ~ 'd.JMe mo M::h trtJSde shoUd not excood 0.1 mt To patlaru., haWig ~ respcnse. ~tatY ~ oould be giv8n. To~ ~..ants. the do$8 cen be repeated CT J'lcr66Hd lm~gulorty. EM for~ rrusdli tle maxnun dow shct*.f be less UTen 5 U I ifl. The OiiU1Jon o1 BTXA The cUilltlOn of BlXA w:th st61fi& nDm1llll seine ftUd be dorw cartJUY on the bas:ISofraal tl99ds.. ~ ~ ar~tabled~to b81'9C01lllll01lcb t

10.0U / 0.1 rnl 5...0 U / 0.1ml !..SU / 0.1 ml 1..21U I 0.1 ml

-.... .. -tmii..-50U'Iill 100U-..ial

8.0""

Shaldro h M gont2y a.,_~ state ronW saline to tno ~to dluot>klg. Tha toconstitutod BTXA si'IOI.ild be used ill cn::o or SXltfld t1 rOttgora!Or at 2 to 8"c and to bo usod wilhk'l 4 hotn. Tho c:ontanor iW'Id 1he S)'t'ngt used wJh hi m.g as woll as tho ~ BTXA sol6::rl anc:Udbe dsposed efter Qrization. SIDE EFFECTS T611'()0r8•y ptosis. of the eyeijd, chwbec:kof h t:MMer e;eid. nKb:::ed ~. eyeld c:lrJse ~dy. ~of f.ecial muscles. e:c ~OCCll' to a Jew pe:Jell'iS who reooNed 6TXA lhOrapy fa ~and twntac:ial spasm. Howovor, all tho symptoms will ~)Q81' ·wfthout aJ'If hnpyW'*' 3 10 8 W8l!lks ~and di~ dl999 d ptosis of thO oyolld, vortlcal dovia1lon and rwaly n'l)d'asis. ~ mlllt8d to the dlkJston at thG lx:»cin lo the~ ac1ara1nt. mey oc<:ur to some pebents wl'lO rocEII.ved BTXA lt'ler8i7Y fOr $b'8b;$m.l$ The~ wll di8;Jpeer ~ eny \t'.erl!Pf ~n 3 few weeks CONTRAINDICATIONS 6TXA i$ ~ W\ ~ lMitl ~c oonstiUlOn Wid lcroM't hypnans..l.Y.ty flO hS PfOPDI'atJOn. PRECAUTIONS B'n<A most bo kOpt, fssuod. ~~ by IJ)80ial PIJ1IQn fW'd aci'rw1tstar8d O"lly Ia tho potlo•~ls with Dhow nctcallons. Pnyslca't& ~ ~ 4ft1g tho lroalt'n.OM c:A strabiSIT'IUI, 1-.-e to be hined piOr< lcnowextraoculet 3nd fec;al muSCleS anatcrnv and be good at~~ tec:f'nQ.Je The~ pocecbe should be teken later to pat.ents whO have fever, acute nectOA ~end aw&U'f to the petienta with hoM. ... ~ c:beue&. Kl~ ~blood daoesos and (JIOQMI'lt W()f'non. Botullr&Jm tom mev bO~ ~ ~ nti:ltlca (loch 0$ gonuwnlcln). This kind of dlug& JhoUd not bo liken clrilg ....... tuM otSTXA. BTXAia In lOw elf«:t Or oMttoJt any elleC:t 10 h pe»r.a: i"' O'le k.llfowhg am.~ strel)i$mus ~ 50 j)li$m diootert.. fxed S)~ o..er.."t. aytdCime dus to we&k teterot rOCb..il, strebiSI'IlJS C3UMd by exces.s1vely OlrT8Cted ~ d'wCnC per~ Ill'~. c:h-onlc VI 01 lA ctM'1III nDM ~atys.s. -'cui muscta that conhctlno. 1:1000 w·onaloo sJ)oUd bo ~od n CU8 01 occ:asiDI'W 8CICdlnt.. Short porkxt ol ot>sorvaucn Is rooommondod to U'IO petl!na v.flo ~ t8CQMid B'TXA f¥Jd1Dn. HOW SUPPUEO 100 U 1 VIal, 50 U I V,eJ SHn.F UF'E 3 ~tom the date of ~etkln STORAGE Store et tOO'IPOI8.tUIO oi...S 10 ·2(/c Q3 to _..d- MANUFACTURER Leru:hou lnat.tu•.o of Blologlcel Products SOLE AGENT 1-\!gh Sclu'c:e ~ Ud let ~ 2n 181322 Fex 18521211!252<9 J:mol. ~.oom

HUiiH 11111 1111111111111111111111111111111111111111111111111111111111111111

Hugh Source (International) Limited

Flat 1311-1312, 13/F, New East Ocean Centre, 9 Science Museum Road, Tsim Sha Tsui, Kowloon, Hong Kong. Tel: 852-2771 6622 Fax: 852-2782 5249 http://www.btxa.com Email: hughs@hughsource.com